Lilly and Alkermes are finalizing the late-stage development plan for their inhaled insulin following Lilly's decision to step up its investment in the companies' pulmonary insulin collaboration.

"Lilly has made a positive product decision and will proceed with significant investment for the further development of an inhaled formulation of insulin," the companies announced Aug. 10.

The decision was contingent on achieving several "critical steps," including completion of a Phase II trial, successful commercial manufacturing scale-up, and development of a commercial pulmonary insulin inhaler system, the companies noted.

The late-stage development program will include both Phase II and Phase III trials, Lilly and Alkermes said.

Under the April 2001 agreement, Lilly has exclusive worldwide commercial rights to Alkermes' inhaled insulin formulation. Lilly is responsible for trials and regulatory submissions, while Alkermes is responsible for manufacturing and device development.

The formulation uses Alkermes' AIR pulmonary dry powder delivery technology, administered via a small inhaler.

The "recently completed" Phase II trial of the product in 120 patients with type 1 diabetes showed that patients achieved similar levels of glycemic control to injected insulin, the companies reported.

The inhaled formulation also had a "rapid onset of action" and "was well tolerated with adverse events similar in both treatment arms," Lilly and Alkermes said.

Based on the bumpy development path of other inhaled insulin products, safety and efficacy are both bound to be key issues in determining product viability: the NDA for Pfizer/Aventis/Nektar's Exubera has been delayed since 2001 due to pulmonary safety concerns, while Phase III results for Novo Nordisk/Aradigm's AERx iDMS inhaled insulin system NN-1998 revealed a delay in post-meal glucose suppression (¹ Also see "Novo Nordisk/Aradigm Inhaled Insulin Study For Type 1 Diabetes Raises Efficacy Concern" - Pink Sheet, 30 April, 2004.).

A European submission for Exubera, announced in March, is pending (² Also see "Pfizer/Aventis File For Exubera In Europe; No Timeline Yet On U.S. Submission" - Pink Sheet, 4 March, 2004.).

As a leader in injectable insulin, Lilly has been seeking to add a non-injectable form of insulin to its franchise for some time.

The company discontinued Phase II trials of a previous inhaled insulin formulation in 2001 after terminating an agreement with Elan for its Spiros pulmonary delivery technology. Lilly exited a collaboration to develop Generex' RapidMist aerosolized oral (buccal) liquid spray insulin Oral-lyn (formerly Oralin ) in May 2003.

Generex has continued development of Oral-lyn, now in Phase IIb in Canada, without Lilly, and is looking for a new U.S. partner. Generex expects the regulatory path for buccal insulin to be smoother than that for inhaled formulations (³ Also see "Oralin Buccal Insulin May Face Easier Regulatory Path Than Inhaled Insulins, Generex Consultant Predicts" - Pink Sheet, 10 February, 2004.).

At least three other inhaled insulins are in clinical development (in addition to Exubera and NN-1998) - Coremed's Alveair , Kos' breath-activated metered dose inhaler formulation and Bristol-Myers Squibb/QDose's inhaled formulation - but none have reached Phase II, according to F-D-C Reports' ⁴ NDA Pipeline .

Besides inhaled insulin, Lilly's collaboration with Alkermes includes an AIR inhaled formulation of human growth hormone (in Phase I) and a long-acting formulation of Lilly/Amylin's anti-diabetic exenatide (exenatide LAR, in Phase II) using Alkermes' Medisorb sustained-release drug delivery technology.

- Alla Rutstein Bobbitt

Lilly/Alkermes Inhaled Insulin To Enter Late-Stage Development

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